BEZ235 as a dual PI3K/mTOR inhibitor

by Selleckchem | Sep 23 2012

Characterization of BEZ235
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway involves in various cellular processes including cell growth, proliferation, survival, and metabolism. is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. BEZ235, also known as NVP-BEZ235, is a potent and highly specific oral dual mTOR/PI3K inhibitor. BEZ235 structure reveals that it is an imidazoquinoline derivative, and is shown to be toxic to Waldenström's macroglobulinemia cells. [1] BEZ235 has the solubility around 7 mg/mL in dimethyl sulfoxide (DMSO) however it is scarcely soluble in water and ethanol. And the approximate price of BEZ235 is $170 per 100 mg and BEZ235 price may vary according to the proportion purity of the preparation and/or from one BEZ235 supplier to different ones .

In vitro activity
According to kinase assays in vitro, BEZ235 shows potent inhibitory activity against p110α, p110γ, p110δ and p110β with IC50 of 4 nM, 5 nM, 7 nM and 75 nM, respectively. [2] The colorimetric MTS assay reveals that BEZ235 treatment for 48 hours results in a dose-dependent decrease on cellular viability with IC50 of 14.3 nM, 9.0 nM, and 12.0 nM for HCT116, DLD-1, and SW480 cell lines, respectively. No increase of cleaved caspase-3 and cleaved PARP indicates no effect on cell apoptosis from BEZ235 treatment [7]. Interestingly, the inhibition effect of BEZ235 on mTORC1 and mTORC2 is sustained while the effect on PI3K is transient.

In vivo
Anti-tumor effect of BEZ235 in vivo has also been studied by researchers or scientists. In a genetically engineered mouse (GEM) model for sporadic wild-type PIK3CA CRC, BEZ235 treatment, at a dose of 45 mg/kg by daily oral gavage for 28 days, induces regression of individual colonic tumors with no toxicity or side effects during this drug treatment regimen[3]. Effects of he similar treatment of BEZ235 are also examined by immunohistochemistry for the proliferation and TUNEL assay for cellular apoptosis. The results indicates that in vivo treatment with BEZ235 results in a significant decrease in tumor proliferation, does not induce cellular apoptosis. Since the PI3K and mTOR pathways play a significant role in tumor angiogenesis, the inhibition of the pathway by BEZ235 treatment leads to decrease of microvessel density (MVD) by 75% after 28 days [3]. These findings provide compelling evidence for the further investigation of combination therapy with BEZ235, cytotoxic, and/or anti-angiogenic agents in clinical trials.

REFERENCES
[1] Sacco, A. e.a., Role of dual PI3K/Akt and mTOR inhibition in Waldenstrom's Macroglobulinemia. Oncotarget 2010, 1 (7): 578–582.
[2] Maira, S.M. E.a., Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008, 7(7):1851–1863.
[3] Roper, J. e.a. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer. PLoS One, 2011, 6(9), e25132.

Cat.No.	Product Name	Information
S1039	Rapamycin	Rapamycin is a specific mTOR inhibitor with IC50 of ~0.1 nM in HEK293 cells.Rapamycin binds to FKBP12 and specifically acts as an allosteric inhibitor of mTORC1. Rapamycin is an autophagy activator and an immunosuppressant.
S1009	Dactolisib (BEZ235)	Dactolisib (BEZ235, NVP-BEZ235) is a dual ATP-competitive PI3K and mTOR inhibitor for p110α/γ/δ/β and mTOR(p70S6K) with IC50 of 4 nM /5 nM /7 nM /75 nM /6 nM in cell-free assays, respectively. Inhibits ATR with IC50 of 21 nM in 3T3^TopBP1-ER cell. Dactolisib induces autophagy and suppresses HIV-1 replication. Phase 2.